Neurogenic bladder disease is a disorder involving loss of control of urination. The major symptoms of this disease are urinary frequency, urinary retention or incontinence. There are two types of lesions that cause a neurogenic bladder. The first, upper motoneuron lesion, leads to hypertonia and hyperreflexia of the bladder, a spastic condition, giving rise to symptoms of urinary frequency and incontinence. The second lesion, a lower motoneuron lesion, involves hypotonia and hyporeflexia of the bladder. The major symptoms in this condition are urinary retention, since the voiding reflex has been lost, and incontinence, which occurs when the bladder "leaks", being full to overflowing.
The majority of neurogenic bladder patients have the spastic or hypertonic bladder. The clinician usually attempts to convert the condition of hyperreflexia and hypertonia to hypotonia, thereby treating the primary problem of incontinence. When the condition has been converted to hypotonia, it can be managed by intermittent catheterization. However, there is a significant population of patients who cannot be converted completely from the hypertonic to the hypotonic condition, and who still find they have to urinate every hour or are incontinent. For these patients, treatment with an anticholinergic drug is necessary. The drug of choice is oxybutynin (4-diethylamino-2-butynylphenylcyclohexylglycolate).
The use of oxybutynin chloride, as approved by the FDA in the United States, is described in the 1992 Physician's Desk Reference, pages 1332 through 1333 with reference to the drug Ditropan.RTM. manufacturea by Marion Merrell Dow. Oxybutynin is normally administered to human Deings orally at relatively high doses (5 mg tablets taken two to four times a day). Oxybutynin has been incorporated into tablets, capsules, granules or pills containing 1-5 mg, preferably 5 mg, of oxybutynin chloride, syrups containing 1-5 mg, preferably 5 mg, of oxybutynin chloride per 5 ml and transdermal compositions (creams or ointments) containing 1-10 weight percent ("wt %") oxybutynin chloride. See, BE 902605.
In U.S. Pat. No. 4,747,845, oxybutynin was listed as an agent that could be incorporated into a transdermal synthetic resin matrix system for extended duration drug release, but oxybutynin was not used in the device. In U.S. Pat. No. 4,928,680 oxybutynin was given as a pharmacologically active agent suitable for transdermal delivery, but as with the above reference, oxybutynin was not incorporated into the device.
Oxybutynin has been incorporated into a device having a water impermeable barrier layer, a reservoir containing oxybutynin in contact with the inner surface of the barrier layer and a removable protector layer in contact with the other surface of the reservoir. The reservoir is a polyurethane fiber mat impregnated with an aqueous solution containing 25 mg/ml of oxybutynin. The device was placed on a 20 .mu.m thick polybutadiene film. The non-device carrying surface was in contact with 0.05 M isotonic phosphate buffer solution. The in vitro release rate measured was approximately 12 mg over 24 hours through a 49 cm.sup.2 area or 10 .mu.g/cm.sup.2 /hr. (U.S. Pat. No. 4,784,857 and EP 0 250 125).
In Pharm Res, "Development of Transdermal Delivery Systems of Oxybutynin: In-Vivo Bioavailability", P. Keshary et al., (NY)8 (10 Supp) 1991, p. S205 three types of transdermal delivery systems, using matrix-diffusion controlled and membrane-permeation controlled technologies were discussed. The in vitro permeation rate of about 9, 12 and 12 .mu.g/cm.sup.2 /hr and in vitro release rates (sink condition) of about 1160, 402 and 57.2 .mu.g/cm.sup.2 /hr were obtained from Silastic monolithic, acrylic pressure sensitive adhesive matrix and reservoir type delivery systems, respectively. In humans, steady state plasma concentrations of about 1.86 ng/ml were obtained after 6 hours of application of a single 20 cm.sup.2 patch of the acrylic pressure sensitive adhesive matrix type.
The transdermal route of administration for drugs and other biologically active agents ("agents") has been proposed for a wide variety of systemically acting and locally acting agents on either a rate-controlled or non rate-controlled basis and is described in numerous technical publications and patents, such as U.S. Pat. Nos. 3,598,122; 3,598,123; 3,731,683; 3,797,494; 4,031,894; 4,201,211; 4,286,592; 4,314,557; 4,379,454; 4,435,180; 4,588,580; 4,645,502; 4,704,282; 4,788,062; 4,816,258; 4,908,027; 4,943,435; and 5,004,610. The disclosures of the above patents are incorporated herein by reference.
Just as certain drugs can irritate, sensitize or be otherwise toxic, so can permeation enhancers. The use of permeation enhancers for transdermal administration is described in numerous technical publications and patents, such as U.S. Pat. Nos. 4,940,586; 4,863,738; 4,820,720; 4,746,515; 4,568,343; 4,405,616; 4,379,454; 4,343,798; 4,335,115; 4,299,826; 4,130,667; 4,130,643; 4,046,886; British Patent No. 1,001,949 and Idson, Percutaneous Absorption, J. Phar. Sci., Vol. 64, No. 66, June 1975, pp. 901-924.
Permeation enhancers that are not normally toxic at the concentrations employed in cosmetic or medical compositions may exhibit toxic effects at the higher concentrations required to produce adequate permeation enhancement. No "universal" permeation enhancer has been identified. Instead, the behavior of permeation enhancers is highly idiosyncratic; a permeation enhancer effective for one drug may not be effective with other drugs, including closely related drugs.
Often, a permeation enhancer will exacerbate irritation and sensitization problems by allowing high transdermal permeation rates of the drug or permeation enhancer or permitting otherwise impermeable components of the transdermal device to enter the skin. Many potential permeation enhancers interact adversely with other components of transdermal devices. One major problem is that many potential permeation enhancers are not compatible with medically acceptable contact adhesives. Enhancers may improve the transdermal permeation rate adequately, but not adequately reduce the lag time.
The use of a permeation enhancer in any transdermal drug delivery device necessarily complicates the design and development of the device. Permeation enhancers cause compatibility problems throughout the delivery system. Instead of having to characterize the properties of the reservoir compositions, adhesives, and release-controlling materials with respect to just the drug, these materials must now have the proper characteristics with respect to both the drug and the permeation enhancer. Typically, drugs and permeation enhancers have very different physical and chemical properties, and, in most cases, the properties of mixtures of the drug with the permeation enhancer are unknown. For example, permeation enhancers can cause, among other problems, cohesive failure of adhesives and can partition through other components in the system.
As used herein, the term "oxybutynin" is used to designate oxybutynin, acid addition salts of oxybutynin and the related compounds thereof. The preferred active agent according to the present invention is oxybutynin itself. Oxybutynin is a base capable of forming acid addition salts with organic and mineral acids, for example, with hydrochloric acid to form oxybutynin chloride. Preferably, the device of this invention contains oxybutynin as the free base.
As used herein, the term "transdermal" delivery or application refers to the delivery or application of oxybutynin by passage through skin, mucosa and/or other body surfaces by topical application.
As used herein, the term "therapeutically effective" amount or rate refers to the amount or rate of oxybutynin needed to effect the desired therapeutic result.
As used herein, the term "monoesters" refers to those monoesters having from 10 to 20 carbon atoms.
As used herein, the term "glycerol monooleate" refers to glycerol monooleate itself or a mixture of monoglycerides wherein glycerol monooleate is present in the greatest amount.
As used herein, the term "glycerol monolaurate" refers to glycerol monolaurate itself or a mixture of monoglycerides wherein glycerol monolaurate is present in the greatest amount.
As used herein, the term "glycerol monolinoleate" refers to glycerol monolinoleate itself or a mixture of monoglycerides wherein glycerol monolinoleate is present in the greatest amount.
The above summarizes the primary characteristics recognized to date that affect suitability of oxybutynin and a permeation enhancer for transdermal administration. There are undoubtedly others, some of which have not yet been recognized. In order for oxybutynin and a permeation enhancer to be suitable for transdermal administration they must possess the right combination of all of these characteristics, a combination which is quite rare and unpredictable.